Hemoglobin (Hb) Val de Marne (Hb Footscray) in Brazil: the first case report.

Hemoglobin (Hb) variants involving alpha-chains are less common in the global population than Hb variants resulting from beta-chain alterations. Generally, alpha-chain Hb variants are caused by point mutations affecting alpha-1 and/or alpha-2 genes of the alpha-globin cluster (HBA1 and HBA2). In Brazil, the most prevalent alpha-chain Hb variant is Hb Hasharon. In this study, we present the first case of an Hb Val de Marne variant in the Americas, specifically in Brazil.

High failure rate of the dissolution tests for 500-mg amoxicillin capsules sold in Cambodia: is it because of the product or the test method?

OBJECTIVES: During the survey of substandard medicines in Cambodia in 2007, it was found that more than 90% of 500-mg amoxicillin (AMPC) capsules failed the United States Pharmacopeia (USP) 30 TEST 1 dissolution test. In the USP, several monographs provide multiple methods for performing the dissolution test. By using the 500-mg AMPC capsule as an example, we aimed to identify the problems and implications of the USP methods adopted for the dissolution test as a global standard. METHODS: All AMPC samples were collected from the Cambodian market in 2007. For the quantitative test, we referred to USP 30. We performed the USP 28 and USP 30 TEST 2 dissolution tests and compared these results with those of the USP 30 TEST 1. RESULTS: All 500-mg AMPC capsules used for the comparison passed the quantitative test. Samples that passed the USP 28 and USP 30 TEST 2 dissolution tests were identical, and the pass rate was 97.1% (34/35), whereas the pass rate with the USP 30 TEST 1 was 8.6% (3/35). The difference in the dissolution results between the three methods was significant (P<0.0001). CONCLUSION: This study revealed that many users would select the most stringent method when multiple methods exist in the USP. This may lead to a high failure rate of the tests. Because USP is a global standard, we recommend that it take into consideration the developing countries and create a more detailed user-friendly manual for selection for appropriate methods.

Maintenance behaviour and long-lasting insecticide-treated nets (LLITNs) previously introduced into Bourapar district, Khammouane province, Lao PDR.

BACKGROUND: Long-lasting insecticide-treated nets (LLITNs) are expected to be an important advance in malaria control, but operational experience is still scarce. This study presents some operational findings concerning the introduction of Olyset LLITNs (Sumitomo Chemical Co., Ltd, Japan) in Laos. The study site, Bourapar district, a remote district at high risk of malaria, received Olyset nets during 1999-2000. After distribution of the nets the number of malaria cases in the district hospital decreased for a time, however it began to rise again a year after the intervention. To sustain the effect of the nets, net users were given instructions on maintenance and use. This study aimed to investigate the condition of Olyset nets and the maintenance behaviour of net users after 2-3 years of use, and to examine the associations between maintenance behaviour and the number of malaria episodes during the previous year. METHODS: Questionnaire interviews and inspections of nets were conducted at 240 households during February-March 2003. RESULTS: About 40% of the observed nets had holes/were torn, and the maintenance instructions had not been followed sufficiently. Households following the recommended washing frequency (38.2%) reported fewer malaria episodes during the past year, which demonstrates the importance of the recommended washing frequency in the effective use of the nets. CONCLUSIONS: Our study promotes the idea that, in addition to pursuing high coverage of LLITNs, more effort should be made to ensure that nets are kept in good condition in future LLITN programmes.

Influence of the 2014-2015 Ebola outbreak on the vaccination of children in a rural district of Guinea.

Setting: All health centres in Macenta District, rural Guinea. Objective: To compare stock-outs of vaccines, vaccine stock cards and the administration of various childhood vaccines across the pre-Ebola, Ebola and post-Ebola virus disease periods. Design: This was an ecological study. Results: Similar levels of stock-outs were observed for all vaccines (bacille Calmette-Guérin [BCG], pentavalent, polio, measles, yellow fever) in the pre-Ebola and Ebola periods (respectively 2760 and 2706 facility days of stock-outs), with some variation by vaccine. Post-Ebola, there was a 65-fold reduction in stock-outs compared to pre-Ebola. Overall, 24 facility-months of vaccine stock card stock-outs were observed during the pre-Ebola period, which increased to 65 facility-months of stock-outs during the Ebola outbreak period; no such stock-out occurred in the post-Ebola period. Apart from yellow fever and measles, vaccine administration declined universally during the peak outbreak period (August-November 2014). Complete cessation of vaccine administration for BCG and a prominent low for polio (86% decrease) were observed in April 2014, corresponding to vaccine stock-outs. Post-Ebola, overall vaccine administration did not recover to pre-Ebola levels, with the highest gaps seen in polio and pentavalent vaccines, which had shortages of respectively 40% and 38%. Conclusion: These findings highlight the need to sustain vaccination activities in Guinea so that they remain resilient and responsive, irrespective of disease outbreaks.

Contexte: Tous les centres de santé de la Préfecture de Macenta, en Guinée rural.Objectif: Comparer la rupture en vaccins, en cartes de stock de vaccins et l'administration des différents vaccins d'enfance pendant les périodes pré-Ebola, Ebola et post-Ebola.Schéma: Une étude écologique.Résultats: Des niveaux similaires de rupture étaient observés pour tous les vaccins (bacille Calmette-Guérin [BCG], pentavalent, polio, rougeole, fièvre jaune) dans les périodes pré-Ebola et Ebola (respectivement 2760 et 2706 jours-structure de rupture), avec quelques variations par vaccin. Post-Ebola, il y avait 65 fois plus de réduction en rupture, comparé à la période pré-Ebola. Un total de 24 mois-structure de rupture en cartes de stock de vaccins était observé pendant la période pré-Ebola, qui a augmenté à 65 mois-structure de rupture pendant la période Ebola ; une telle rupture ne s'est pas produite dans la période post-Ebola. Excepté la fièvre jaune et la rougeole, l'administration de vaccin a diminué universellement pendant la période de pointe de l'épidémie (août­novembre 2014). L'arrêt complet de l'administration de vaccin pour le BCG et une baisse marquée pour la polio (diminution de 86%) étaient observés en avril 2014, correspondant à une rupture de vaccins. Post-Ebola, l'administration globale de vaccins n'a pas atteint les niveaux pré-Ebola, avec les plus grands écarts observés aux niveaux de la polio et du pentavalent (respectivement des baisses de 40% et 38%).Conclusion: Ces résultats soulignent le besoin de maintenir les activités de vaccination en Guinée afin qu'elles restent résilientes et réactives, indépendamment de l'épidémie d'une maladie.

Marco de referencia: Todos los centros de atención de salud del distrito de Macenta en una zona rural de Guinea.Objetivo: Comparar el desabastecimiento de vacunas, las tarjetas de existencias de vacunas y la administración de las diversas vacunas de la infancia durante diferentes períodos, en función de la epidemia de fiebre hemorrágica del Ébola, a saber: antes, durante el brote y después del mismo.Método: Un estudio ecológico.Resultados: Se observaron niveles equivalentes de desabastecimientos de todas las vacunas (BCG, pentavalente, antipoliomielítica, antisarampionosa y antiamarílica) antes de la epidemia del Ébola y durante la misma (2760 y 2706 días de desabastecimiento por establecimiento, respectivamente), con alguna variación en función de las vacunas. En el período posterior a la epidemia se presentó una tasa de desabastecimientos 65 veces menor, en comparación con el período anterior a la epidemia. En general, se observaron 24 meses-centro de desabastecimiento en las tarjetas de existencias vacunales durante el período pre-Ébola, que aumentaron a 65 meses-centro de desabastecimiento durante la epidemia; en el período posterior al brote no ocurrió este tipo de desabastecimiento. Con la excepción de la vacuna antiamarílica y la antisarampionosa, la administración de vacunas disminuyó globalmente durante el período de máxima actividad de la epidemia (de agosto a noviembre del 2014). Se observó una interrupción total de la administración de BCG y una tasa considerablemente baja de administración de vacuna antipoliomielítica (disminución de un 86%) en abril del 2014, que correspondió con el desabastecimiento de vacunas. Después de la epidemia del Ébola, la administración general de vacunas no recuperó el nivel anterior al brote y las mayores carencias se observaron con la vacuna antipoliomielítica y la pentavalente (40% y 38% de déficit, respectivamente).Conclusión: Los resultados del presente estudio destacan la necesidad de sostener las actividades de vacunación en Guinea, de manera que conserven su capacidad de recuperación y de respuesta, con independencia de los brotes epidémicos.

Nitric oxide controls feeding behavior in the chicken.

To investigate the effect of nitric oxide (NO) on food intake in the chicken, L-NG-nitro-arginine methyl ester HCl (L-NNA), an inhibitor of NO synthase, was applied. When i.p. administered, L-NNA significantly inhibited the food intake of broiler chickens in a dose response manner. Food ingestion was also depressed by the i.c.v. injection of L-NNA in a dose response fashion. The effect of L-NNA was attenuated by i.c.v. administration of L-arginine. These results suggest that central NO may control feeding behavior in the chicken.

Intracerebroventricular injection of mammalian and chicken glucagon-like peptide-1 inhibits food intake of the neonatal chick.

Glucagon-like peptide-1 (GLP-1), structurally similar to glucagon, is synthesized from a larger precursor, preproglucagon, and has been postulated to be a novel incretin. Recently, it was reported that central administration of GLP-1 decreased food intake in rats. The amino acid sequences of GLP-1 are identical in all mammals, and chicken GLP-1 exhibits a high homology with mammalian GLP-1. The aim of this study was to elucidate whether central injection of mammalian or chicken GLP-1 inhibits food intake in the chick, and to compare their effects. Intracerebroventricular administration of mammalian and chicken GLP-1 strongly inhibited food intake of chicks. However, the suppressive effect of both GLP-1 on food intake was similar. These results show that GLP-1 with a variety of amino acid sequences may be the most potent inhibitor of food intake in the chicken.

The interaction of clonidine and nitric oxide on feeding behavior in the chicken.

Central administration of alpha 2-receptor agonists stimulate food intake in mammalian and avian species. Recently we reported that inhibition of nitric oxide (NO) synthase (NOS) decreased food intake in chickens. In the present study, we investigated whether the increased eating induced by clonidine (Clon), an alpha 2-receptor agonist, is attenuated by NOS inhibition. In the first experiment, four levels (0, 9.4, 18.8 or 37.5 nmol/10 microliters) of Clon were administered into the right lateral ventricle of chickens, and food intake was monitored. Clon increased 30 min-food intake in a dose-dependent manner. In a co-administration study of L-NG-nitro-arginine methyl ester HCl (LNNA), a NOS inhibitor, and Clon, LNNA (0, 1.5, 3.0 or 5.9 mumol) attenuated food intake induced by Clon (37.5 nmol) in a dose-dependent manner. Our results suggest the possibility that NO interacts with adrenergic neurons in the central nervous system to modulate feeding behavior in the chicken.

Inhibition of food passage by omeprazole in the chicken.

The effect of omeprazole, a proton pump inhibitor, on the forward passage of the crop contents of chicks receiving 20% medium chain or long chain triacylglycerol was studied. Medium chain triacylglycerol significantly delayed the crop emptying of chicks compared with long chain triacylglycerol. Omeprazole also significantly inhibited passage from the crop of the long chain triacylglycerol meal. Application of omeprazole induces achlorhydria and consequently hypergastrinemia but chicken gastrin lower than 100 nmol/kg did not delay crop emptying. The addition of hydrochloric acid (HCl) to the diet reversed the action of omeprazole on the crop emptying of chicks. We conclude, then, that omeprazole delayed the crop emptying in chicks as a consequence of inhibition of acid secretion, although the mediator is not gastrin.

Aspirin promotes hepatic triacylglycerol accumulation in essential fatty acid-deficient Japanese quail.

This study was conducted to investigate whether the effect of a high dose of aspirin on hepatic triacylglycerol content is altered by dietary essential fatty acids (EFA) in Japanese quail. The birds were given an EFA-free or EFA-adequate [containing 2% (w/w) linoleic acid] diet ad libitum from 7 to 24 days of age. On the final experimental day, the birds received vehicle or 800 mg aspirin/kg body weight intraperitoneally and were killed 4 h subsequently. In birds fed the EFA-free diet, hepatic triacylglycerol content was more than 2 times higher after aspirin compared with vehicle treatment; in contrast, aspirin had no affect in birds fed the EFA-adequate diet. Liver malic enzyme and phosphatidate phosphohydrolase activities, which are related to lipid synthesis, were not affected by dietary EFA or aspirin treatment. Liver carnitine palmitoyltransferase activity in the birds fed the EFA-free diet was significantly lower than that in the birds fed the EFA-adequate diet, but aspirin did not affect this activity. In groups given the EFA-free diet, peroxisomal beta-oxidation was increased by the aspirin treatment. We conclude that acute administration of aspirin to Japanese quail on an EFA-free diet induces hepatic triacylglycerol accumulation, and that changes in lipid synthesis and degradation do not contribute to this phenomenon.

Factors regulating amylase secretion from chicken pancreatic acini in vitro.

In mammals, cholecystokinin regulates pancreatic exocrine secretion under physiological conditions. We have shown, however, that cholecystokinin at physiological concentrations does not induce pancreatic amylase secretion in birds. Therefore, we investigated the effects of various neurotransmitters and gut hormones on the pancreatic amylase secretory response in isolated chicken pancreatic acini. Acetylcholine (half-maximal stimulation at 800 nM) and vasoactive intestinal polypeptide (half-maximal stimulation at 40 pM) produced a concentration-dependent increase in amylase secretion at physiological concentrations. The combination of acetylcholine and vasoactive intestinal polypeptide produced an additive response in amylase secretion. Sodium nitroprusside, a spontaneous nitric oxide releaser, and bombesin, induced amylase secretion at concentrations greater than 10 nM and 100 nM, respectively. Gastrin and secretin increased amylase secretion at pharmacological concentrations (10 to 100 nM). Our findings suggest that neural regulation is important for pancreatic enzyme secretion in birds and the contribution of gut hormones seems to be physiologically unimportant.

Mineral balance and bone histology in spontaneously hypertensive rats.

SHRs (9 weeks old) were fed diets with or without extra NaCl (2%) and were given water or saline (1%) for 7 weeks. Food and liquid intakes were measured weekly. Blood pressure was determined at 9, 11, 13, 15, and 16 weeks of age. The values for body weight gain and food intake were not influenced by any treatment. Liquid intake greatly increased with the surplus of dietary NaCl. The blood pressure increased with age in all treatments. The increase in blood pressure was enhanced by the addition of NaCl to diet and water. Urinary potassium and calcium excretions were enhanced by added dietary NaCl and saline. Calcium content in the femoral bone was not changed by any treatment, although the number of osteoclast and the area of bone marrow were increased by saline supplementation.

Feeding behavior in growing rats fed diets containing sorbose.

The effect of dietary sorbose on food and water consumption was investigated in growing rats. Rats (26-day old) were fed diets containing 0, 100, 200 or 300 g sorbose/kg diet for 5 weeks in Experiment 1. Daily food and water intakes were measured at day 0, 7, 14, 21, 28 and 35. Absolute food intake (g) until day 21 decreased linearly with increasing sorbose levels and so did relative food intake (g/100 g b.wt.) until day 7. In contrast, relative water intake (ml/100 g b.wt.) and water:food intake ratio (ml/g) remained high by day 7 with increasing sorbose levels. In Experiment 2, the effect of sorbose on the short-term food intake was compared with those of glucose, sucrose and maltitol in growing rats (25-day old) at a level of 100 g/kg diet in order to investigate how quickly reduced food intake would be induced by sorbose consumption. Cumulative food intake was determined every hour for the first ten hours, then at two-hour intervals thereafter during the 24-hour period that followed feeding. As rapid as 6 hours after feeding, cumulative food intake significantly decreased in sorbose-fed animals compared with other dietary groups. It was concluded that sorbose consumption decreased the food intake of growing rats from 6 hours to a few weeks after feeding, but this inhibitory effect disappeared afterwards.

Feeding behavior in rats fed diets containing medium chain triglyceride.

The effect of dietary medium chain triglyceride (MCT) on short-term food intake was compared with the effect of long chain triglyceride (LCT) in rats. Corn oil and glyceryl tricaprylate were used as LCT and MCT sources, respectively. Rats were given diets containing 200 g MCT/kg diet (MCT diet), 100 g MCT + 100 g LCT/kg diet (ML diet), or 200 g LCT/kg diet (LCT diet) in Experiment 1. Cumulative food intake was determined every h for the first 12 h, then at 2-h intervals thereafter during the subsequent 12 h. As early as 1 h after feeding, cumulative food intake significantly decreased in MCT-fed animals in a dose-dependent fashion. In Experiment 2, rats were given a choice between MCT and LCT diets for 1 h to confirm whether or not the palatability of diets was influenced by dietary fat sources. There was no difference in food intake between the two diets. In Experiment 3, the responsibility of endogenous cholecystokinin (CCK) for the difference in food intake between the two diets was investigated for 6 h by using a CCK-A receptor antagonist, Devazepide (DVZ, 1 mg/kg b. wt.). Food intake in the MCT diet and also in the LCT diet was improved by DVZ. It is concluded that the satiety, but not the palatability, is affected by carbon chain length in dietary triglyceride sources, although the responsibility of endogenous CCK is very small.

The role of olfaction in oil preference in the chicken.

The role of olfaction on the preference of diets containing 20% medium-chain (MCT) or long-chain triacylglycerol (LCT) was investigated in the chicken. Olfactory bulbectomized, sham-operated (Sham) or intact (Intact) birds were offered a choice between LCT or MCT diet and food intake was measured over a short time period. Intact and Sham groups showed a significant preference for LCT over MCT diet, but olfactory-bulbectomized chickens lost the preference for LCT over MCT. The bilateral cutting of the olfactory nerves confirmed the results taken in olfactory bulbectomy. It is concluded that olfaction plays a major role in the preference of diets containing MCT or LCT in chickens.

Aspirin toxicity in chicks given diets deficient in linoleic acid.

The toxicity of dietary aspirin on growth rate and lipid metabolism was investigated under linoleic acid (LA; 18: 2n-6) deficient conditions. One-week-old chicks were given diets containing 0 or 2% LA with or without 0.4% aspirin, until 4 weeks of age. Growth was severely depressed by dietary aspirin when chicks were given the LA-free diet. The liver was enlarged by both the aspirin and LA deficiency. The aspirin treatment induced a significant increase of 18:0 and arachidonic acid (20: 4n-6) and a decrease of 18: 1n-9 in the liver. In chicks fed LA-free diets, the ratio of 20:3n-9/20: 4n-6, which was used as an indicator of LA deficiency, was suppressed by aspirin treatment. In conclusion, the present results suggest that aspirin toxicity is altered by dietary LA concentrations.

Cephalosporins. II. 7-(O-Aminomethyl-phnylacetamido) cephalosporanic acids with six membered heterocycles in the C-3 side chain.

7-(o-Aminomethylphenylacetamido)cephalosporanic acids with six-membered heterocycles in the C-3 side chain were prepared by nucleophillic substitution of 7-ACA at the C-3 acetoxy group followed by N-acylation of the 7-amino group. The 7-side chain acid, o-aminomethylphenylacetic acid (5), was prepared by two new convenient routes, which involved Schmidt reaction of indanone (2) followed by cleavage of the lactam ring or reduction of o-cyanophenylacetic acid (10) starting from o-nitrotoluene. The antibacterial activity of the cephalosporins in this series depends on the heterocycle in the C-3 side chain. In general pyridazines gave cephalosporin derivatives possessing better activity than those with a pyridine or pyrimidine ring. The most active member of the new cephalosporins was 7-(o-aminomethylphenylacetamido)-3-(6-hydroxypyridazin-3-ylthilmethyl)-3-cephem-4-carboxylic acid (BB-S 150) (1g) which has in vitro antibacterial activity superior to cephalothin and cefazolin against both gram-negative and gram-positive organisms. The in vitro activity of BB-S 150 determined in mice was superior to cephalothin and comparable to cefazolin.

Cephalosporins. I. Cephaloglycin analogs with six-membered heterocycles in the C-3 side chain.

Cephaloglycin analogs with six-membered heterocycles in the C-3 side chain have been prepared by nucleophilic substitution of 7-aminocephalosporanic acid with appropriate azine thiols followed by 7-N-acylation with phenylglycine by the mixed anhydride method. Seventeen thiols of non-substituted or substituted pyridines, pyridazines, pyrimidines, pyrazines and triazines were used as the S-nucleophiles. In general, pyridazine thiols gave cephalosporins processing good antimicrobial activity against both gram-positive and gram-negative bacteria. Among them 6-hydroxypyridazine-3-thiol gave the most active compound of this series, BB-S 118 (1f), which was significantly more active than cephalexin and cephaloglycin in vitro against gram-positive and gram negative bacteria.

Cephalosporins. III. 7-(O-Aminomethylphenylacetamido)cephalosporanic acids with bicyclic heteroaromatics in the C-3 side chain.

Bicyclic heteroaromatic thiols with a bridge-head nitrogen atom were used for nucleophilic substitution of 7-ACA at the C-3 acetoxy function followed by N-acylation of the 7-amino group with o-aminomethylphenylacetic acid to afford a series of new cephalosporins (24) with potent antibacterial activity against gram-positive and gram-negative organisms. The most active member of this series was 7-(o-aminomethylphenylacetamido)-3-(tetrazolo-[4,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acid (BB-S 226) (24e) with antibacterial activity superior activity superior to cephalothin and cefazolin.

Synthesis and structure-activity relationships of a new oral cephalosporin, BMY-28100 and related compounds.

The synthesis and structure-activity relationships of 7-[D-alpha-amino-alpha-(4-hydroxyphenyl)-acetamido]-3-[(Z)-1-propenyl]- 3-cephem-4-carboxylic acid (BMY-28100) and its analogs in the 3- and 7-side chains are described. The 3-(substituted-propenyl) groups were introduced by the Wittig reaction of the 3-phosphoniomethyl cephems which were derived from the 3-chloromethyl derivatives. The reaction gave predominantly the cis isomer regarding the 3-side chain. The cis and trans isomers showed characteristic UV and 1H NMR spectra. Most of cephems of this series were well-absorbed orally and more active both in vitro and in vivo than cephalexin and cefaclor against Gram-positive organisms. Their Gram-negative activity varied depending on the 3- and 7-substituents. Compounds with a cis-propenyl group showed the best Gram-negative activity among the 3-alkenyl analogs prepared, whereas the D-4-hydroxyphenylglycyl and D-4-hydroxy-3-methoxyphenylglycyl substitutions in the 7-side chain were found suitable to improve the Gram-negative activity of 3-cis-propenyl series of cephalosporins to the level favorably compared with that of cefaclor. The 3,4-dihydroxyphenyl analog was found to be metabolized in vivo to the 4-hydroxy-3-methoxyphenyl derivative and, therefore, showed nearly the same in vivo activity as that of the latter. BMY-28100 was selected for further evaluation and the results will be reported in the subsequent paper.

Synthesis and structure-activity relationships of a new series of cephalosporins, BMY-28142 and related compounds.

The synthesis of a series of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-oxyiminoacetamido] -3-ammoniomethyl-3-cephems is described. Variations of an oxyimino moiety in the 7-side chain and a quaternary ammonium moiety in the 3-side chain were examined and structure-activity relationships studied. BMY-28142, the 3-(N-methylpyrrolidinio)methyl derivative of the 7-alpha-methoxyimino series of cephalosporins, exhibited broad antimicrobial activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.